This is an application for a K23 award for Dr. Katherine Possin, a neuropsychologist at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Possin is establishing herself as a young investigator in patient-oriented clinical research of spatial cognition in neurodegenerative disease. This K23 award will provide Dr. Possin with the support necessary to accomplish the following goals: (1) to become an expert in the behavioral neurology of neurodegenerative disease;(2) to conduct clinical investigations of spatial cognition in neurodegenerative disease by adapting innovative methods from cognitive neuroscience;(3) to develop proficiency in advanced multimodal neuroimaging analyses;and (4) to develop an independent clinical research career. To achieve these goals, Dr. Possin has assembled a mentoring team comprised of a primary mentor, Dr. Bruce Miller, Director of the MAC, who conducts clinical investigations in neurodegenerative disease as the PI on a Program Project Grant (PPG) on Frontotemporal Dementia and an Alzheimer's Disease Research Center (ADRC);and three co-mentors: Dr. Joel Kramer, a neuropsychologist who is an international leader in the development of neuropsychological tests;Dr. Maria Luisa Gorno Tempini, a neurologist with expertise in structural MRI including diffusion tensor imaging;and Dr. William Seeley, a neurologist with expertise in resting state functional connectivity MRI. Spatial cognitive deficits are often among the earliest symptoms of neurodegenerative disease, yet spatial function tests used in current dementia evaluations lack the anatomic specificity to differentiate between pathologic causes of dementia including Alzheimer's disease (AD), Parkinson's disease (PD) with cognitive impairment, and behavioral variant Frontotemporal dementia (bvFTD). Early diagnosis is more than merely of academic interest due to the contraindication of neuroleptic drugs in PD and the promise of molecule-specific treatments on the horizon. Dr. Possin's research will dissect the specific components of spatial function targeted by each disease using rigorous assessment methods developed and validated within a cognitive neuroscience framework, including virtual reality navigation tests (Aim 1), and her research will elucidate the neural correlates of spatial performance using structural and diffusion tensor imaging analyses (Aim 2). In addition, her research will identify the functional neural networks related to important aspects of spatial processing that are disrupted in these diseases (Aim 3). The proposed research will use the existing infrastructure of the PPG and the ADRC to enroll 31 patients with early AD, 31 patients with PD, 31 patients with bvFTD, and 31 neurologically healthy controls. Via the parent projects, a rich dataset will be made available to Dr. Possin for analysis with the spatial cognitive data that includes multimodal neuroimaging, general neuropsychological testing, neurological exam, and functional evaluation data. Public health relevance the results from this study will inform anatomically-specific methods for spatial assessment in dementia evaluations, and will provide valuable information about the neural substrates of spatial cognition. PUBLIC HEALTH RELEVANCE: Spatial cognitive deficits are often among the earliest symptoms of neurodegenerative disease, yet spatial function tests used in current dementia evaluations lack the anatomic specificity to differentiate between neurodegenerative disorders. Tools developed through this research program will improve the early differential diagnosis of dementia, inform sensitive methods of spatial assessment for clinical trials, assist clinicians in treatment monitoring, and predict real-world spatial functioning such as driving skills. Additionally, this work will help to link basic science studies of spatial cognition to the clinic and will provide valuable information about the neural substrates of spatial cognition.